Upon exposure to most antigens, an individual responds by synthesizing specific antibodies that subsequently may interact with the inciting antigens and unite noncovalently with them to form immune complexes (ICs). This course of the normal immune response is designed to eliminate and/or neutralize the antigens, thus benefiting the host. However, there is no doubt that formation of ICs under some circumstances is detrimental to the host.
The harmful effects of ICs were first suggested at the beginning of this century by von Pirquet (1911), who proposed that the onset and course of serum sickness were determined by toxic factors produced by the interaction of host antibody and antigen in the circulation. Thereafter, others made similar observations (Longcope, 1915; Rich and Gregory, 1943; Hawn and Janeway, 1947). The definite pathogenic role of the ICs was shown during the 1950's by the work of Germuth (1953), Germuth and McKinnon (1957), Germuth et al (1957), Dixon and associates (1958, 1961), and Dixon (1963), who confirmed and amplified von Pirquet's original theory using the experimental rabbit model of "one shot" serum sickness. It was demonstrated that the onset of glomerulonephritis and generalized vasculitis coincided with the appearance of soluble ICs in rabbits' circulations, a decrease in serum complement (c) activity, and a deposition of ICs in the sites of injury (Dixon, 1963; Dixon et al, 1958, 1961).
In vivo and in vitro experiments have more recently clarified many factors involved in IC formation, removal, and localization as well as the mechanisms of IC-induced inflammatory reactions. Moreover, ICs are now viewed, apart from their potential phlogogenicity, as regulators of both cellular and humoral immune responses by virtue of their capacities to interact with antigen receptor-bearing lymphocytes and subpopulations of T and B cells, as well as with unclassified lymphocytes and macrophages having Fc and C receptors. With the recognition of the immunopathologic consequences of ICs and the development of new techniques for demonstrating ICs in tissues and biological fluids, considerable evidence has accumulated substantiating the primary pathogenic significance of ICs in a variety of animal and human diseases.
Circulating soluble ICs in man and lower animals are responsible for, or associated with, a diverse array of diseases. These include autoimmune disease, neoplastic diseases, infectious diseases due to bacteria, viruses and parasites, and other unclassified disorders.
Both exogenous and endogenous antigens can trigger pathogenic immune responses, resulting in IC disease. The awareness of IC's important role in many diseases has stimulated development of techniques for demonstrating them in tissues and biological fluids.
The presence of ICs in pathologic tissue specimens can be inferred from several lines of evidence. Histologically, the patterns of injury may appear similar to those known to occur in experimental animals in which IC disease has been induced (Wilson and Dixon, 1976). Presumed IC deposits in tissues can be identified also by electron microscopy and by conventional histochemical techniques. Of the immunohistochemical techniques, the most widely used is immunofluorescence (Wilson and Dixon, 1976), which allows Ig, C components, and in some cases specific antigens, to be identified. When these materials deposit in a granular, discrete pattern, in all likelihood the individual has an IC disorder. In addition, if enough of the diseased tissue is available, deposited ICs can be eluted from it by using low pH buffers (citrate buffer, HCI-glycine buffer) (Oldstone, 1975a; Koffler et al, 1971; Woodroffe and Wilson, 1977; Bartolotti, 1977) or chaotropic agents (KI, KSCN) (Edgington, 1971; Woodroffe and Wilson, 1977), etc., after which the antibodies and sometimes the antigens can be recovered, quantitated, and identified (see Section VI).
Recently, interest has increased in developing immunologic techniques for demonstrating ICs directly in bodily fluids.
Although historically the development of assays for soluble ICs started with physiochemical rather than immunologic techniques, the latter are more commonly used now. It is useful to divide all the available methods into two main groups; antigen-specific tests, that is, detection of a specific antigen complexed with antibody or, by far the larger and more readily applicable group, antigen-nonspecific tests.